Abstract Defective intestinal epithelial tight junction (TJ) barrier has been postulated to play an important pathogenic role in a wide variety of inflammatory conditions, including alcoholic liver disease. Our preliminary studies suggest that chronic alcohol consumption causes an increase in intestinal permeability and that the increase in intestinal permeability is required for the development of liver disease. The overarching goals of this grant application are to: a) investigate the pathogenic mechanisms that mediate alcohol consumption - associated increase in intestinal permeability, b) delineate the causal linkage between defective intestinal TJ barrier and development of liver inflammation, and c) investigate the therapeutic role of probiotic bacteria Lactobacillus acidophilus (LA) in targeting the intestinal TJ barrier to prevent liver inflammation. The primary focus of the grant proposal will be on the gut-liver axis interaction or on the role of defective intestinal TJ barrier in the pathogenesis of liver inflammation and injury. Based on our compelling preliminary data, we advance a paradigm-shifting hypothesis that gut-derived bacterial lipopolysaccharide (LPS) is an etiologic factor responsible for the alcohol consumption-associated increase in intestinal permeability and the subsequent development of liver disease. We also hypothesize that therapeutic targeting of intestinal TJ barrier is both sufficient and effective strategy to prevent alcoholic liver disease. We also advance a novel hypothesis that LA inhibits the alcohol consumption - associated increase in intestinal permeability and the subsequent development of liver disease via a TLR2 signal transduction pathway suppression (not activation) of enterocyte NF-KB p50/p65 and MLCK gene activation. Two specific aims are proposed to address the above hypotheses: 1) to determine the pathogenic role of defective intestinal TJ barrier in the development of liver disease and to delineate the mechanisms that mediate the increase in intestinal TJ permeability and 2) to determine the therapeutic efficacy of probiotic bacterial targeting of intestinal TJ barrier to prevent or treat liver disease and to delineate the protective mechanisms involved. The successful completion of the proposed studies will provide important new insight into the integral role gut-liver axis plays in the pathophysiology of alcohol-induced liver injury and also provide crucial pre-clinical data needed to support future clinical studies.